Drs. Jay Levy and Don Des Jarlais have conducted a pilot study examining the possibility that a substantial percentage of injection drug users (IDUs) exposed to HIV do not become infected. The reason for this protection is not known, but they hypothesize that it could be related to innate immune responses. This type of immune activity, which occurs rapidly after interacting with a pathogen, has protected other individuals exposed to HIV by non-intravenous routes of transmission (see below). In the pilot study, seven of thirty uninfected IDUs (23%) showed an innate CD8+ cell anti-HIV response. This CD8+ cell noncytotoxic antiviral response (CNAR) has only been observed in people exposed to or infected by HIV. CNAR could be responsible for this protection from infection. The purpose of this proposal is to conduct an in-depth study of this important observation on IDUs. Included is further evaluation of the association of high-risk behavior in IDUs to CNAR, and to explore other innate immune activities, particularly those of plasmacytoid dendritic cells and NK cells and immune activation as possible factors that influence resistance to infection. The Specific Aims of the proposed research are as follows: 1. Determine the prevalence of the CD8+ cell noncytotoxic antiviral response (CNAR) among HIV seronegative IDUs with a high likelihood of recent (past year) exposure to HIV through injecting risk behavior and with low likelihood of exposure to HIV through sexual risk behavior. We will test the hypothesis that IDUs with a high likelihood of recent exposure to HIV through injecting risk behavior will have a higher prevalence of CNAR than will IDUs with a low recent risk for injecting risk and low sexual risk exposure to HIV. 2. Determine whether other innate anti-HIV characteristics, such as the number of NK cells, plasmacytoid dendritic cells and immune activation are associated with potential protection from infection in HIV seronegative IDUs. These aims will be achieved by obtaining additional blood samples from 160 subjects to be enrolled in the Risk Factors study: 80 IDUs with high injecting and low sexual risk for recent HIV exposure, 40 IDUs, with low injecting and low sexual risk, 20 HIV negative non-injecting drug users, and 20 HIV seropositive IDUs. Our pilot work indicates that approximately one quarter of injecting drug users may have innate immune responses that can protect against HIV infection. Understanding such innate immune responses could contribute greatly to the epidemiology of HIV among injecting drug users and may provide critical information for the development of new therapies for HIV infection and a possible HIV vaccine. PUBLIC HEALTH RELEVANCE: This project focuses on natural immune anti-viral responses that can be important in preventing HIV infection and thus limiting its spread throughout the world.